It is proposed to study the role of cellular membranes in the cytotoxicity of the antineoplastic agent adriamycin. Although the paradigm for the mechanism of action of this drug has been interference with DNA function, a variety of experiments suggest that membrane actions may be equally or more important. To further explore this idea we have covalently linked adriamycin to agarose beads. This immobilized adriamycin will be used to study the interaction of the drug with the plasma membrane of cultured tumor cells without permitting the drug to penetrate the cell interior. In order to clarify the molecular mechanisms of drug-membrane interaction, it is also proposed to carry out some physiochemical studies of the interaction of adriamycin with liposomes. These experiments are designed to answer such basic questions as how does adriamycin alter membrane fluidity, where in the bilayer does the bound drug reside, what is the kinetic mechanism of interaction, what intermediates are formed and what are their lifetimes, and what is the time scale of adriamycin binding to phospholipid bilayers? Moreover, evidence for a role of the phospholipid cardiolipin in drug specificity is presented and experiments aimed at exploring the phenomenon are described. A second aspect of this work proposes to alter plasma membrane lipid composition via fusion with liposomes with consequent effects on the action of anticancer drugs. The rationale of this approach is that introduction of new lipid components into the surface membrane of a growing cell may alter its permeability or specificity towards any pharmacologic agent or influence its role as the primary receptor for the drug. To test this hypothesis we will systematically assess the ability of a variety of liposome types to alter the cytotoxic action of selected antineoplastic drugs on tumor cells in culture. This approach differs from the more common use of liposomes as drug carriers, for here we propose to use liposomes as drugs themselves in combination chemotherapy with other agents.